Parkinson's disease (PD) is debilitating neurodegenerative disorder that affects millions of people in the US and worldwide. PD is due to a deficiency of the neurotransmitter dopamine, caused by selective destruction of dopaminergic neurons in the mid-brain substantia nigra. The etiology of PD remains largely unexplained, despite continued intense basic science and epidemiologic investigation. There is, however, increasing experimental and epidemiologic evidence that environmental toxicants are etiologically related to the development of PD. Recent thinking on PD causation also emphasizes the significance of gene/environment interactions, whereby persons who carry genotypes predictive of either a diminished capacity for chemical detoxification or an enhanced propensity to activate pro-neurotoxicants are most susceptible to environmentally-induced PD. Selection of candidate genes in PD research should be guided both by epidemiologic knowledge of environmental risk factors and an understanding of the underlying pathogenic mechanisms of PD. During the past 20 years, there has accumulated a substantial body of evidence demonstrating the importance of several inter-connected pathogenic mechanisms?abnormal dopamine metabolism, oxidative stress, and neuroinflammation?that contribute to the destruction of dopaminergic neurons. We are proposing to continue and extend our ongoing population-based case-control study of PD. The study will ultimately include 600 incident PD cases and 900 age- and gender-matched unrelated controls selected from the enrollment of the Group Health Cooperative health maintenance organization in the Puget Sound region of Washington state. Our project will involve the following components: 1) investigation of associations of PD risk with environmental factors, including those that occur at hazardous waste sites (e.g., pesticides, metals), and lifestyle factors (e.g., smoking, diet); 2) testing associations with previously established plausible candidate gene variants pertinent to dopamine metabolism, oxidative stress, and neuroinflammation; 3) testing gene/environment and gene/gene interactions; and 4) performing replication analyses of genetic associations observed in our study with data from three similar, yet independent, PD case-control studies. The findings that prove to be reproducible across studies should offer great potential to shed light on the causal pathways of this complex disease, and should ultimately inform disease prevention strategies. Furthermore, this project may serve as model approach for investigating the complex interplay between low-level environmental exposures, as would be anticipated to result from hazardous waste sites, and host susceptibility factors on risk for major neurodegenerative disorders.